Hospital-associated respiratory virus infections (HA-RVI) lead to increased morbidity, mortality, and healthcare costs, but these infections are often under- or misdiagnosed particularly for respiratory viruses other than influenza. HA-RVI are preventable through appropriate treatment and infection control measures, but incomplete diagnosis leads to missed opportunities for intervention. Taking advantage of these opportunities for intervention might require additional diagnostic testing and expanded infection control measures. The degree to which these approaches would be cost-effective is unclear. Therefore, there is a need to define the burden and clinical impact of respiratory viruses in the hospital setting to inform optimal diagnostic, treatment and infection prevention strategies. The overall objective of this project is to support Josh Petrie, PhD in the development of expertise in healthcare epidemiology, state-of-the-art molecular methods, and advanced modeling techniques. This objective will be completed through focused training and career development activities in healthcare epidemiology, next generation sequencing, bioinformatics, cost-effectiveness analysis, and mathematical modeling that is overseen by an excellent team of mentors. The skills developed by the training and career development objectives will be strengthened by mentored research to accomplish the following Specific Aims: (1) Define the epidemiology and burden of community-acquired and hospital- associated respiratory virus infections and compare clinical impact by viral species; (2) Improve the sensitivity and specificity of case definitions to identify hospital-associated influenza cases by integrating clinical, epidemiologic, and molecular data; and (3) Determine the cost-effectiveness of increased respiratory virus screening and expanded infection control measures to reduce HA-RVI using mathematical models. Completion of the training and research programs will represent the next step on Dr. Petrie's path toward achieving his long term goal of establishing an independent research program that uses multidisciplinary laboratory and analytic methodologies to investigate the transmission of influenza and other respiratory viruses. The expected research outcomes of the proposed project are, 1) identification of respiratory viruses that, in addition to influenza, are responsible for the greatest number of HA-RVI and result in the most severe clinical outcomes; 2) development of methodology for improved identification of HA-RVI through integration of clinical, epidemiologic, and molecular data; and 3) determination of cost-effective diagnostic testing and intervention implementation strategies for HA-RVI prevention. The proposed research is significant because it is expected that the outcomes of this work and future studies that build upon it, will lead to reductions in morbidity, mortality, and healthcare costs associated with HA-RVI. This research is innovative both in its focus on a large panel of important respiratory viruses and its use of cross-disciplinary methodology that allows for new avenues of research.